CN109020942A - 具有抗肿瘤活性的异色满酮类化合物、其制备方法及用途 - Google Patents
具有抗肿瘤活性的异色满酮类化合物、其制备方法及用途 Download PDFInfo
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- CN109020942A CN109020942A CN201810817835.4A CN201810817835A CN109020942A CN 109020942 A CN109020942 A CN 109020942A CN 201810817835 A CN201810817835 A CN 201810817835A CN 109020942 A CN109020942 A CN 109020942A
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- methoxyl group
- trimethoxyphenyl
- hydroxyl
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Abstract
本发明涉及药物化学领域,具体涉及一类具有抗肿瘤活性的异色满酮类化合物。本发明还公开了含有所属化合物的药用组合物和所述化合物在治疗肿瘤以及通过抑制微管蛋白活性来治疗其他疾病或病症中的应用。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类具有抗肿瘤活性的异色满酮类化合 物。本发明还公开了含有所属化合物的药用组合物和所述化合物在治疗肿瘤以及 通过抑制微管蛋白活性来治疗其他疾病或病症中的应用。
背景技术
微管是细胞骨架的主要组成部分,在维持细胞形态、细胞分裂、信号转导等 过程中起着重要作用,因此,微管蛋白是非常有前景的新型化疗药物的靶标。微 管蛋白抑制剂能阻止肿瘤细胞的过度增殖,是一类重要的抗肿瘤治疗药物。目前, 临床上应用的微管抑制剂主要有以紫杉醇为代表的抑制微管蛋白解聚药物及以 长春碱类为代表的抑制微管蛋白聚集药物。但这些药物存在毒副作用大、合成困 难、水溶性差、易产生耐药性等缺点。秋水仙碱结合位点是目前对微管蛋白研究 较多的一个位点,作用于该位点的抑制剂通常结构较简单,如秋水仙碱、 Combretastatin A-4等。此外,作用于该位点的抑制剂还能破坏肿瘤组织的血管, 因此,对作用于秋水仙碱位点的微管蛋白抑制剂的研究已成为当今抗肿瘤研究的 热点。
我们前期研究发现,从香蕉皮中提取得到的异色满酮类化合物XJP及其类 似物有着广泛的药理活性,如降血压、抗炎及抗氧化作用(参见Liu J,Ren H,Xu J,et al.Totalsynthesis and antihypertensive activity of(±)7, 8-dihydroxy-3-methyl-isochromanone-4.Bioorganic&medicinal chemistry letters, 2009,19(6):1822-1824;Fu R,Chen Z,Wang Q,et al.XJP-1,a novel ACEI,with anti-inflammatory propertiesin HUVECs.Atherosclerosis,2011,219(1):40-48.)。后 续的研究发现,XJP衍生物8-羟基-7-甲氧基异色满-4-酮具有体外抗微管蛋白聚 集活性(IC50=10.62μM),且对HepG2肿瘤细胞株显示了微弱的抗增殖活性(IC50=21.6μM)。
三甲氧基苯基为微管蛋白抑制剂的优势药效团,常被用于新型微管蛋白抑制 剂的设计。为提高8-羟基-7-甲氧基异色满-4-酮的抗微管及抗肿瘤活性,我们在 该结构的4位上引入了三甲氧基苯基片段,设计合成了一类含异色满酮骨架的微
发明内容
本发明的目的旨在寻找活性好,毒性小,对耐药肿瘤有效的含异色满酮骨架 的新型微管蛋白抑制剂,并提供该类化合物的制备方法及用途。
为实现上述目的,本发明提供如下技术方案:
1、一种具有抗肿瘤活性的异色满酮类化合物,及其可药用盐,具有通式I所示 的结构:
其中:
X选自氧、硫、硒、不同烷基取代的氮;
R1选自氢、低级烷烃、羟基、氨基、甲氧基、卤素、氰基、酯基、酰胺基, 羧基,硼酸基、磷酸二钠盐,氨基酸;
R2选自氢、羟基、氨基、甲氧基、卤素;
双键或还原双键,当双键还原时,Y碳原子可为R构型或者S构型。
2.在本发明一个优选的实施方案中,
X优选氧、硫、硒;
R1优选氢、甲氧基、羟基、氨基、溴、磷酸二钠盐、氨基酸;
R2优选氢、羟基、氨基;
3.双键或还原双键,当双键还原时,Y碳原子可为R构型或者S构型。
本发明的部分优选化合物为:
实施例1:7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例2:7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例3:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例4:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例5:7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例6:7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例7:7-甲氧基-8-溴-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例8:7-甲氧基-8-溴-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例9:6-羟基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例10:6-羟基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例11:7-甲氧基-8-氨基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例12:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异硫色满;
实施例13:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异硒色满;
实施例14:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1,2,3,4-四氢异喹啉;
实施例15:R-7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例16:S-7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例17:R-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满-8-羟基磷酸二钠盐;
本发明通式I的化合物可用下列方法制备得到:
反应1
反应2
A.反应1合成步骤如下:
原料1于DMF中经钠氢拔氢后与Weinreb酰胺2反应得到中间体Weinreb 酰胺3,3在叔丁基锂条件下发生自身的环合反应得到各种取代的异色满-4-酮4; 苄醇原料5经三溴化磷溴代得到溴苄6,再与新制备的二硫化二钠或二硒化二钠 水溶液反应得到中间体7。7经硼氢化钠还原后与溴乙酸乙酯反应得到8,再水 解经草酰氯反应制备酰氯后,通过与四氯化锡发生傅克反应得到异硫色满酮与异 硒色满酮10;原料11与甘氨酸甲酯制备Schiff碱后经硼氢化钠还原可得到中间 体13,13水解成羧酸,随后在正丁基锂条件下发生自身环合得到14。各种酮与 对甲苯磺酰肼在乙醇中发生缩合反应得到磺酰腙15,然后经钯催化的偶联反应 与三甲氧基溴苯16反应得到各种取代的中间体异色原烯17。
B.反应2的合成步骤如下:
苄基保护的中间体18可在THF中采用氢气/钯碳条件选择性脱苄基得到含异 色原烯骨架的终产物19;而在甲醇中采用氢气/钯碳条件可得到含异色满骨架的 终产物20。
下面是本发明部分化合物的药理实验结果:
抗增殖实验
1.实验方法
2.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液,96孔板中每孔 加入100μl细胞悬液(每孔5×103个细胞);
3. 96孔板置于37℃,5%CO2培养箱中培养24小时;
4.用完全培养基稀释药物至所需浓度,每孔加入100μL相应的含药培养基;
5. 96孔板置于37℃,5%CO2培养箱中培养72小时;
6.MTT法:
1)将96孔板进行MTT染色,λ=490nm,测定OD值。
2)每孔加入20μL MTT(5mg/mL),在培养箱继续培养4小时;
3)弃去培养基,每孔加入150μL DMSO溶解,摇床10分钟轻轻混匀;λ=490 nm,酶标仪读出每孔的OD值。
6.计算抑制率。
2.实验结果
表1通式I中的实施例对3种人类癌细胞株抗增殖活性的IC50值(μM)
下面是部分化合物的体外抗微管蛋白聚集的实验
1.实验方法
化合物按照相应要求配置成母液,按照倍数稀释成终浓度后用于后续试验。 浓度设置为5个,每个浓度生物学重复3次。将2mg/mL微管蛋白(细胞骨架) 的量重新悬浮于PEM缓冲液[80mM PIPES(pH6.9),0.5mM EGTA,2mM MgCl2和15%甘油]中,然后在冰上与化合物或溶剂DMSO预孵育5分钟。在检测微管 蛋白聚合反应之前,加入含有GTP的PEG至终浓度为3mg/mL。通过Berthold LB941微孔板式多功能酶标仪,30分钟后在340nm检测吸光度。通过设置空白 对照组,Graphpad计算得出不同化合物的IC50,结果以μM为单位。
2.实验结果
表2本发明部分化合物的体外微管蛋白聚集的药理实验结果:
下面是部分化合物的体内抗肿瘤实验
1.实验方法
由上海斯莱克实验动物有限责任公司提供,周龄为3周,体重12-16g的雌 性Balb/c裸鼠70只。收集培养的肝癌H22细胞,计数、调整使细胞悬液浓度为 1.5×107个/ml,于裸小鼠右侧腋窝皮下每只接种0.1ml。用游标卡尺测量裸鼠移 植瘤的直径,接种肿瘤细胞7天后,肿瘤长至50-75mm3时,每组10只将裸鼠 随机分为7组。衍生物溶于DMSO,再滴入poloxamer母液,最后加生理盐水至 所需剂量。DMSO终浓度为1%,poloxamer终浓度为2%。各组裸鼠给药,模 型组腹腔注射等量溶媒,每天注射1次,持续21天;阳性对照组尾静脉注射30 mg/kg顺铂,每天注射1次,持续21天;实验组静脉注射30mg/kg化合物3,4, 11,12,13,14。每天注射1次,持续21天;给药21天结束后处死裸鼠,通过手 术剥取瘤块,称重。计算肿瘤生长抑制率(%),用SPSS 17.0对结果进行分析, 组间用t检验进行统计学分析处理,其计算公式如下:
2.实验结果
表3部分实施例的体内抗肿瘤活性
具体实施方式
以下通过实施例形式展示具体的实施方式,对本发明内容进行进一步的详细 说明,但不应当将此理解为本发明上述主题的范围仅限于以下的实施例,凡是基 于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
实施例1
7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯
(a)将间甲氧基苯甲醛(2g,14.7mmol)溶于50ml甲醇中,分批加入NaBH4(556 mg,14.7mmol),室温搅拌十五分钟,饱和氯化铵溶液淬灭,旋掉甲醇,乙 酸乙酯稀释,水洗,饱和食盐水洗,无水Na2SO4干燥,浓缩得2.06g无色 油状间甲氧基苯甲醇;
(b)将a的产物(2g,14.5mmol)溶于50mL甲苯与50mL 40%的氢氧化钾水溶液 的混合溶液中,随后加入四丁基溴化铵(47mg,1.4mmol),滴入溴乙酸乙酯(3.5 g,17.4mmol),室温搅拌,反应结束后旋掉甲苯,乙酸乙酯稀释,水洗,饱和食 盐水洗,无水Na2SO4干燥,浓缩得粗品;该粗品溶于无水甲醇中,滴入甲醇钠 的甲醇溶液20mL,室温搅拌,反应结束后加水继续搅拌15分钟,停止反应, 旋掉甲醇,乙酸乙酯稀释,水层酸化后,继续用乙酸乙酯萃取三次,合并后干燥 浓缩得白色固体2.5g,产率89.3%。
(c)将b的产物(2.3g,11.7mmol)溶于干燥的二氯甲烷中,加入5滴DMF作催 化剂,0度条件下缓慢滴入草酰氯(1.2mL,14.1mmol),室温搅拌30分钟后, 旋掉溶剂,溶于无水氯苯中,氮气保护下滴入四氯化锡(1.7mL,14.0mL)搅拌 两小时,旋掉氯苯,二氯甲烷稀释,饱和食盐水洗,无水Na2SO4干燥,浓缩后 柱层析(PE/EA 5∶1)得白色固体900mg,产率45%。
(d)将d的产物(300mg,1.69mmol)溶于无水乙醇中,加入对甲苯磺酰肼(375 mg,2.01mmol),90度条件下搅拌,反应结束后抽滤得黄色固体385mg,产率 81%。
(e)将d的产物(200mg,0.58mmol)溶于二氧六环中,依次加入三甲氧基溴苯(173mg,0.7mmol),二乙腈二氯化钯(21mg,0.06mmol),Xphos(28mg,0.06mmol), 叔丁醇锂(93mg,1.16mmol),90度封管反应2h,结束后抽滤,滤液浓缩后柱 层析(PE/EA 10∶1)得白色固体150mg,产率79.3%。1H NMR(300MHz,CDCl3) δ6.99(d,J=8.5Hz,1H),6.75(dd,J=8.5,2.7Hz,1H),6.69-6.60(m,2H),6.58(s, 2H),5.07(s,2H),3.89(s,3H)3.85(s,6H),3.81(s,3H);13C NMR(75MHz, Chloroform-d)δ158.41,152.79,141.26,136.75,131.15,129.66,123.89,123.22, 119.63,112.33,109.96,105.66,68.01,60.42,55.65,54.91;ESI-MS m/z:328.1calcd for C19H20O5[M+H]+329.1.
实施例2
7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满
将实施例1的产物(60mg,0.18mmol)溶于甲醇中,加入6mg钯碳,氢气 条件下搅拌,结束后抽滤,滤液浓缩后柱层析(PE/EA 5∶1)得白色固体33mg, 产率55.0%。1H NMR(300MHz,CDCl3)δ6.85(d,J=8.5Hz,1H),6.64(dd,J= 8.5,2.7Hz,1H),6.50(d,J=2.7Hz,1H),6.31(s,2H),4.78(q,J=15.0Hz,2H), 4.06(dd,J=10.9,4.9Hz,1H),3.95(q,J=6.9Hz,4.8Hz,1H),3.80(q,J=6.9Hz, 4.8Hz,1H),3.76(s,3H),3,72(s,9H);13C NMR(75MHz,CDCl3)δ157.56,152.65, 138.49,135.33,130.13,127.72,112.62,108.07,105.40,71.84,68.09,60.30,55.60, 54.74,43.62;ESI-MS m/z:330.15calcd for C19H22O5[M+H]+331.15.
实施例3
7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯
(a)原料1(2g,9.3mmol)溶于无水DMF中,氮气保护,冰浴条件下加入60% 的钠氢(446mg,11.2mmol),十五分钟后滴入原料2(2g,11.2mmol),室 温搅拌,反应结束后倒入水中,乙酸乙酯萃取三次,水洗三次,饱和食盐水 洗一次,浓缩后柱层析(PE/EA 2∶1)得白色固体2.2g,产率74.8%;该中间 体(2.2g,7.0mmol)溶于无水THF中,-78度条件下,加入叔丁基锂的正己 烷溶液(12mL,16.0mol),反应10分钟后加入氯化铵淬灭,旋掉THF,乙 酸乙酯稀释,水洗,饱和食盐水洗,干燥,浓缩后柱层析(PE/EA 5∶1)得920 mg白色固体,产率60%。
(b)参照实施例一(d,e)的操作,可得苄基保护的前体;将该中间体(100mg,0.23mmol)溶于无水THF中,加入10mg钯碳,氢气条件下搅拌,结束后抽滤, 滤液浓缩后柱层析(PE/EA 5∶1)得白色固体75mg,产率82.0%。1H NMR(300 MHz,DMSO-d6)δ8.95(s,1H),6.82(d,J=8.4Hz,1H),6.74(s,1H),6.60(s, 2H),6.45(d,J=8.4Hz,1H),5.07(s,2H),3.78(s,3H),3.77(s,6H),3.69(s,3H); 13C NMR(75MHz,DMSO-d6)δ152.81,147.06,141.66,141.23,134.44,131.28, 123.99,119.22,115.41,113.14,110.33,105.85,62.53,59.97,55.76;ESI-MS m/z:344.13 calcd for C19H20O6[M+H]+345.13.
实施例4
7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色满
将实施例1(b)的中间体(100mg,0.23mmol)溶于甲醇中,加入10g钯碳, 氢气条件下搅拌,结束后抽滤,滤液浓缩后柱层析(PE/EA 5∶1)得白色固体66mg, 产率65.0%。1HNMR(300MHz,DMSO-d6)δ8.75(s,1H),6.77(d,J=8.4Hz,1H), 6.47(s,2H),6.33(d,J=8.4Hz,1H),4.70(t,J=10.6Hz,2H),3.95(s,2H),3.92- 3.78(m,1H),3.74(s,3H),3.68(s,6H),3.61(s,3H);13C NMR(75MHz,DMSO-d6) δ153.09,145.44,141.57,139.75,129.71,122.57,119.79,110.73,106.56,71.08, 64.74,60.38,56.27,43.51;ESI-MS m/z:346.14,calcd for C19H22O6[M+H]+347.14.
实施例5
7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯
参照实施例3,1H NMR(300MHz,CDCl3)δ6.75(s,2H),6.62(s,1H),6.58(s, 1H),5.21(s,2H),3.89(s,3H),3.86(s,12H);13C NMR(75MHz,CDCl3)δ152.76, 151.39,143.70,141.44,136.74,131.13,124.53,121.98,119.21,117.75,110.64, 105.76,62.79,60.41,55.64,55.33;ESI-MS m/z:358.14,calcd for C20H22O6[M+H]+ 359.14.
实施例6
7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满
参照实施例4,1H NMR(300MHz,CDCl3)δ6.77-6.69(m,2H),6.38(s,2H), 5.00-4.85(m,2H),4.09(dd,J=10.7,4.9Hz,1H),4.02(m,1H),3.91(m,1H),3.87 (s,3H),3.85(s,3H),3.83(s,3H),3.80(s,6H);13C NMR(75MHz,CDCl3)δ152.64, 149.85,143.51,138.36,128.91,128.28,124.29,110.58,105.44,71.22,64.51,60.30, 59.68,55.62,55.25,43.61;ESI-MS m/z:360.2,calcd for C20H24O6[M+H]+361.2.
实施例7
7-甲氧基-8-溴-4-(3,4,5-三甲氧基苯基)-1H-异色原烯
实施例1(c)的产物(500mg,2.8mmol)与水中,分别加入NBS(524mg,3.3 mmol)及40%的硫酸(300μL),60度搅拌,反应结束后,乙酸乙酯萃取,水 洗,饱和食盐水洗,干燥,浓缩后柱层析(PE/EA 10∶1)得产物420mg,产率58.4%;将该产物按照实施例一(e)的方法合成得到目标产物。1H NMR(300MHz, CDCl3)δ6.94(d,J=8.5Hz,1H),6.75(d,J=8.6Hz,1H),6.63(s,1H),6.55(s,2H), 5.27(s,2H),3.89(s,6H),3.85(s,6H);13C NMR(75MHz,CDCl3)δ154.41,152.84, 141.63,136.89,130.65,129.49,125.62,121.80,118.76,110.12,109.37,105.81, 267.52,60.43,55.90,55.66;ESI-MS m/z:406.0 calcd for C19H19BrO5[M+H]+407.0.
实施例8
7-甲氧基-8-溴-4-(3,4,5-三甲氧基苯基)-1H-异色满
参照实施例4,1H NMR(300MHz,CDCl3)δ6.92(d,J=8.5Hz,1H),6.85(d,J =8.6Hz,1H),6.55(s,2H),5.23(s,2H),4.49(dd,J=10.7,4.9Hz,1H),4.08(m,1H), 3.92(m,1H),3.89(s,6H),3.85(s,6H);13C NMR(75MHz,CDCl3)δ154.41,152.84, 141.63,136.89,130.65,129.49,125.62,121.80,118.76,110.12,109.37,105.81, 267.52,60.43,55.90,55.66;ESI-MS m/z:409.0 calcd for C19H21BrO5[M+H]+409.0.
实施例9
6-羟基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯
参照实施例3的合成方法,1H NMR(300MHz,DMSO-d6)δ8.96(d,J=1.2Hz, 1H),7.01-6.38(m,5H),4.97(s,2H),3.86-3.63(m,12H);13C NMR(75MHz, DMSO-d6)δ152.86,146.58,146.07,142.03,131.21,123.80,119.31,119.02,109.78, 109.48,105.85,67.36,66.24,65.92,59.97,55.84;ESI-MS m/z:344.13 calcd for C19H20O6[M+H]+345.13.
实施例10
6-羟基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满
参照实施例4的合成方法,1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),6.63 (s,1H),6.49(s,2H),6.32(s,1H),4.78-4.62(m,2H),4.01-3.91(m,2H),3.80- 3.76(m,1H),3.73(s,3H),3.70(s,6H),3.63(s,3H);13C NMR(75MHz,DMSO-d6) δ152.65,146.39,144.95,139.19,128.05,125.03,115.39,107.71,106.17,106.06, 71.08,67.38,59.89,55.82,55.45,43.02;ESI-MS m/z:346.14 calcd for C19H22O6 [M+H]+347.14.
实施例11
7-甲氧基-8-氨基-4-(3,4,5-三甲氧基苯基)-1H-异色满
参照实施例3的合成方法,可得7-甲氧基-8-硝基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯。该中间体(100mg,0.27mmol)溶于甲醇中,加入10mg钯碳,氢气 下室温搅拌,反应结束后抽滤,浓缩后柱层析(PE/EA 2∶1)得产物75mg,产率 80.6%。1H NMR(300MHz,DMSO-d6)δ6.82(d,J=8.4Hz,1H),6.74(s,1H),6.60 (s,2H),6.45(d,J=8.4Hz,1H),5.32(s,2H),5.07(s,2H),3.78(s,3H),3.77(s,6H), 3.69(s,3H);13C NMR(75MHz,DMSO-d6)δ152.81,147.06,141.66,141.23, 134.44,131.28,123.99,119.22,115.41,113.14,110.33,105.85,62.53,59.97, 55.76;ESI-MS m/z:345.2 calcd for C19H24NO5[M+H]+346.2.
实施例12
7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异硫色满
参照实施例四的合成方法,1H NMR(300MHz,DMSO-d6)δ8.81(s,1H),6.82 (d,J=8.4Hz,1H),6.53(s,2H),6.40(d,J=8.4Hz,1H),4.33(q,J=10.6Hz,2H), 4.20-3.51(m,14H),3.00(m,2H);13C NMR(75MHz,DMSO-d6)δ152.81,147.06, 141.66,141.23,134.44,131.28,123.99,119.22,115.41,113.14,110.33,105.85, 62.80,60.20,59.97,44.5,44.2,27.1;ESI-MS m/z:362.1 calcd for C19H23SO5 [M+H]+363.1.
实施例13
7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异硒色满
参照实施例4的合成方法,1H NMR(300MHz,DMSO-d6)δ8.59(s,1H),6.83 (d,J=8.4Hz,1H),6.63(s,2H),6.42(d,J=8.4Hz,1H),4.10(q,J=10.6Hz,2H), 3.86(m,12H),2.63(m,1H),2.20(m,2H);13C NMR(75MHz,DMSO-d6)δ153.80, 148.12,142.66,140.13,133.44,132.28,122.99,118.12,115.41,113.14,110.33, 105.85,62.80,60.20,59.97,33.5,32.2,21.1;ESI-MS m/z:410.1 calcd for C19H23SeO5[M+H]+411.1.
实施例14
7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1,2,3,4-四氢异喹啉;
参照实施例四的合成方法,1H NMR(300MHz,DMSO-d6)δ8.69(s,1H),6.73 (d,J=8.4Hz,1H),6.62(s,2H),6.3(d,J=8.4Hz,1H),4.10(q,J=10.6Hz,2H), 4.01(q,J=10.6Hz,2H),3.98-3.78(m,13H),3.15(m,2H);13C NMR(75MHz, DMSO-d6)δ152.82,149.13,141.62,140.93,132.44,131.28,123.99,119.12,116.41, 114.14,112.33,105.85,62.80,61.12,60.20,59.97,48.21,43.21;ESI-MS m/z:345.2 calcd for C19H24NO5[M+H]+346.2.
实施例15
R-7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色满
将实施例4溶于乙醇中,进行手性制备。具体条件如下:HPLC:shimadzu LC-20AD(UV dection atλ=214nm);手性柱:CHIRALPAK AD-H(0.46cm I.D.× 15cm L);流速:0.5mL/min;流动相:乙醇。t=8.114min.c=1.0。 1H NMR(300MHz,DMSO-d6)δ8.75(s,1H),6.77(d,J=8.4Hz,1H),6.47(s,2H), 6.33(d,J=8.4Hz,1H),4.70(t,J=10.6Hz,2H),3.95(s,2H),3.92-3.78(m,1H), 3.74(s,3H),3.68(s,6H),3.61(s,3H);13CNMR(75MHz,DMSO-d6)δ153.09, 145.44,141.57,139.75,129.71,122.57,119.79,110.73,106.56,71.08,64.74,60.38, 56.27,43.51;ESI-MS m/z:346.14,calcd for C19H22O6[M+H]+347.14.
实施例16
S-7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色满
参考实施例15的操作。t=4.909min.c=1.0。1H NMR(300MHz, DMSO-d6)δ8.75(s,1H),6.77(d,J=8.4Hz,1H),6.47(s,2H),6.33(d,J=8.4Hz, 1H),4.70(t,J=10.6Hz,2H),3.95(s,2H),3.92-3.78(m,1H),3.74(s,3H),3.68(s, 6H),3.61(s,3H);13CNMR(75MHz,DMSO-d6)δ153.09,145.44,141.57,139.75, 129.71,122.57,119.79,110.73,106.56,71.08,64.74,60.38,56.27,43.51;ESI-MS m/z:346.14,calcd for C19H22O6[M+H]+347.14.
实施例17
R-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满-8-羟基磷酸二钠盐;
实施例4(100mg,0.28mmol)溶于二氯甲烷中,分别滴入三氯氧磷(105μL,1.15mmol)及吡啶(93μL,1.15mmol),室温搅拌15h后,加入饱和碳酸钠水溶 液继续搅拌2h,反应液浓缩,C18柱层析过得产物45mg,产率33.1%。1H NMR (300MHz,D2O)δ7.22(d,J=8.4Hz,1H),6.93(s,2H),6.38(d,J=8.4Hz,1H), 4.68(t,J=10.6Hz,2H),4.15-3.52(m,15H);13C NMR(75MHz,D2O)δ154.09, 145.44,141.57,139.75,129.71,122.57,119.79,110.73,106.56,71.08,64.74,60.38, 56.27,43.51;ESI-MS m/z:470.3,calcd forC19H22Na2O9P[M+H]+471.3.
实施例18
取上述配方,用常规方法制备成片剂。
Claims (5)
1.一种具有抗肿瘤活性的异色满酮类化合物,及其可药用盐,具有通式I所示的结构:
其中:
X选自氧、硫、硒、不同烷基取代的氮;
R1选自氢、低级烷烃、羟基、氨基、甲氧基、卤素、氰基、酯基、酰胺基,羧基,硼酸基、磷酸二钠盐,氨基酸;
R2选自氢、羟基、氨基、甲氧基、卤素;
双键可还原可不还原。
2.在本发明一个优选的实施方案中,
X优选氧、硫、硒;
R1优选氢、甲氧基、羟基、氨基、溴、磷酸二钠盐、氨基酸;
R2优选氢、羟基、氨基。
3.双键或还原双键,当双键还原时,Y碳原子可为R构型或者S构型。
本发明的部分优选化合物为:
实施例1:7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例2:7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例3:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例4:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例5:7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例6:7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例7:7-甲氧基-8-溴-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例8:7-甲氧基-8-溴-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例9:6-羟基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色原烯;
实施例10:6-羟基-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例11:7-甲氧基-8-氨基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例12:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异硫色满;
实施例13:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1H-异硒色满;
实施例14:7-甲氧基-8-羟基-4-(3,4,5-三甲氧基苯基)-1,2,3,4-四氢异喹啉;
实施例15:R-7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例16:S-7-甲氧基-8-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满;
实施例17:R-7-甲氧基-4-(3,4,5-三甲氧基苯基)-1H-异色满-8-羟基磷酸二钠盐。
4.一种药物组合物,其中含有治疗有效量的权利要求1的通式(I)的化合物及药学上可接受的载体。
5.权利要求1的化合物或其盐在制备治疗肿瘤疾病药物中的应用。
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CN109553601A (zh) * | 2019-01-31 | 2019-04-02 | 河南科技大学 | 一种无催化剂法制备5-溴异色满-4-酮的工艺方法 |
CN110407791A (zh) * | 2019-08-22 | 2019-11-05 | 西安石油大学 | α-取代异色满衍生物及其制备方法 |
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CN109553601A (zh) * | 2019-01-31 | 2019-04-02 | 河南科技大学 | 一种无催化剂法制备5-溴异色满-4-酮的工艺方法 |
CN109553601B (zh) * | 2019-01-31 | 2020-11-10 | 河南科技大学 | 一种无催化剂法制备5-溴异色满-4-酮的工艺方法 |
CN110407791A (zh) * | 2019-08-22 | 2019-11-05 | 西安石油大学 | α-取代异色满衍生物及其制备方法 |
CN110407791B (zh) * | 2019-08-22 | 2022-11-15 | 西安石油大学 | α-取代异色满衍生物及其制备方法 |
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